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An Investigation of CYP2D6 Genotype and Response to Metoprolol CR/XL During Dose Titration in Patients With Heart Failure: A MERIT‐HF Substudy
Author(s) -
Batty J A,
Hall A S,
White H L,
Wikstrand J,
Boer R A,
Veldhuisen D J,
Harst P,
Waagstein F,
Hjalmarson Å,
Kjekshus J,
Balmforth A J
Publication year - 2014
Publication title -
clinical pharmacology and therapeutics
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.941
H-Index - 188
eISSN - 1532-6535
pISSN - 0009-9236
DOI - 10.1038/clpt.2013.193
Subject(s) - metoprolol , cyp2d6 , pharmacodynamics , heart failure , medicine , genotype , pharmacology , pharmacokinetics , pharmacogenetics , carvedilol , cardiology , biology , cytochrome p450 , genetics , metabolism , gene
To explore the pharmacogenetic effects of the cytochrome P450 (CYP)2D6 genotype in patients with systolic heart failure treated using controlled/extended‐release (CR/XL) metoprolol, this study assessed the CYP2D6 locus for the nonfunctional *4 allele (1846G>A; rs3892097) in the Metoprolol CR/XL Randomised Intervention Trial in Congestive Heart Failure (MERIT‐HF; n = 605). Participants were characterized as extensive, intermediate, or poor metabolizers (EMs, IMs, or PMs, respectively), based on the presence of the CYP2D6*4 allele (EM: *1*1 , 60.4%; IM: *1*4 , 35.8%; and PM: *4*4 , 3.8%). Plasma metoprolol concentrations were 2.1‐/4.6‐fold greater in the IM/PM groups as compared with the EM group ( P < 0.0001). Metoprolol induced significantly lower heart rates and diastolic blood pressures during early titration, indicating a CYP2D6*4 allele dose–response effect ( P < 0.05). These effects were not observed at maximal dose, suggesting a saturable effect. Genotype did not adversely affect surrogate treatment efficacy. CYP2D6 genotype modulates metoprolol pharmacokinetics/pharmacodynamics during early titration; however, the MERIT‐HF‐defined titration schedule remains recommended for all patients, regardless of genotype. Clinical Pharmacology & Therapeutics (2014); 95 3, 321–330. doi: 10.1038/clpt.2013.193